Genetic Alteration in Key Enzyme Linked to Autism

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Studies in human cell lines and mouse models provide evidence that excess brain activity of the enzyme UBE3A (encoded by the gene UBE3A) increases the risk for autism.

UBE3A is associated with cervical cancer and two neuro-developmental disorders: Angelman syndrome and autism.

The characterization of an autism-linked de novo mutation exclusively affecting UBE3A provides the most direct evidence to date that abnormally elevated levels of UBE3A can increase risk for autism, studies in human cell lines and mouse models now show.

"Our findings suggest that abnormal elevation of UBE3A activity, caused by the T485A missense mutation, contributes to autism pathology in an individual," Mark Zylka, PhD, of the UNC Neuroscience Center at the University of North Carolina at Chapel Hill, N.C., and colleagues reported in Cell.

UBE3A is associated with cervical cancer and two neuro-developmental disorders – Angelman syndrome (AS) and autism -- noted the investigators.

"Our study characterized an autism-linked de novo mutation that hyperactivated UBE3A, possibly mimicking what occurs when the enzyme is duplicated or triplicated," Zylka told MedPage Today. "Importantly, we showed that UBE3A was hyperactive in cells isolated from an autistic individual but not his parents."

Duplication of chromosome region 15q11-q13, known as Dup15q Syndrome, is the third most common cytogenetic event associated with autism (0.25% of all cases of autism spectrum disorder), Zylka said in an interview. This chromosomal region contains UBE3A and a number of other genes.

In previous studies, individuals with an extra maternal copy of 15q11-13 have shown partial autism penetrance while individuals with two extra copies display almost complete penetrance. UBE3A has long been implicated in autism because of this duplication, but whether UBE3A or other genes in the region increase autism risk was unclear, noted Zylka.

"UBE3A is the only gene in this region that is consistently expressed from the maternal, but not paternal, allele in mature neurons, suggesting that abnormally elevated levels of UBE3A contribute to autism in 15q11-13 duplication syndrome," Zylka and colleagues wrote.

The researchers noticed that numerous disease-linked missense mutations in UBE3A were clustered together. In the middle of one of these mutational hot spots was a protein kinase A (PKA) phosphorylation site (T485). "We found that this site can be phosphorylated in vitro, in cells, in neurons, and in the brain and that phosphorylation of this site inhibits UBE3A ubiquitin ligase activity toward itself and its substrates," they said.

The in vitro and in vivo experiments included experiments with lymphocytes from an autism proband harboring a phospho mutant T485A missense mutation. The investigators showed that T485 phosphorylation acts like a master switch that disengages UBE3A from its substrates and blocks UBE3A enzymatic activity.

"Our study shows that UBE3A is regulated by phosphorylation and that an autism-linked mutation disables this phosphorylation control, abnormally elevating UBE3A activity and impairing synapse formation in vivo," said Zylka.

"This has therapeutic implications for patients with Dup15q Syndrome," he added, "as drugs that activate PKA may tamp down UBE3A in these patients with abnormal levels of UBE3A."

While there are drugs that can activate PKA, whether or not these drugs can be used to treat humans or animal models with 15q11-13 duplication/triplication forms of autism has not been evaluated "so more research is warranted," Zylka told MedPage Today.

He added that more research could also shed light on whether mutations that hyperactivate UBE3A, such as the T485A mutation, are linked to additional neuropsychiatric disorders such as developmental delay, depression, and schizophrenia.

Excessive UBE3A activity is also associated with the vast majority of all cervical cancers, Zylka pointed out, "Our findings thus raise the possibility that targeting upstream regulators of UBE3A could provide a general strategy for treating neurological disorders as well as cancer linked to excessive UBE3A activity."

Limitations to the study included its restriction to experiments in animals and cell lines. The relevance to human autism, and the degree to which this genetic factor contributes to the prevalence or severity of autism spectrum disorders on a population basis, remains uncertain.

This work was supported by grants from the Angelman Syndrome Foundation, a Grant-In-Aid from the Foundation for Angelman Syndrome Therapeutics, The Simons Foundation (SFARI Award 274426), the NIMH (R01MH093372),

NINDS (R01NS085093), a NIH Pioneer Award from The National Institutes of Health (DP1ES024088), the NIGMS (P01-GM103723) and a Basic and Clinical Grant (#7760) from Autism Speaks. One investigator is a recipient of the Christina Castellana postdoctoral fellowship of the Foundation for Angelman Syndrome Therapeutics and was supported by NICHD (T32HD040127). The confocal imaging core was funded by grants from NINDS (P30NS045892) and NICHD (U54HD079124).

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